Week 9 Bioscience

Question 1

Sources of drugs: Plants

Answer 1

Plants and plant parts have been used as medicine for centuries and remain an important source of chemicals used for developing into drugs today.
* Morphine - derived from the poppy plant Papaver somniferum →used for pain management
* Digoxin – derived from Digitalis purpurea plant (purple foxglove) →used to slow heart rate and treat congestive heart failure
* Caffeine – derived from the Caffea arabica plant

Question 2

Sources of drugs: Animals

Answer 2

Animal products have been used to replace human chemicals affected by disease or genetic problems.
* Adrenaline - originally obtained from the adrenal glands of monkeys, sheep and cows, now synthesised artificially →used to treat anaphylaxis, cardiac arrest
* Insulin - originally isolated from pigs and cows, now synthesised artificially by genetically modified bacteria →used to treat diabetes

Question 3

Drug names (Drug nomenclature)

Answer 3

Drugs have several names
* The chemical name is a description of the chemical composition of the drug and identifies the drugs atomic and molecular structure, e.g. para-acetyl-amino-phenol C8H9NO2
* The generic (non-proprietary) is the abbreviated and approved name given to a drug by the manufacturer to first develop it, e.g. Paracetamol.
A generic name set by the Therapeutic Goods Administration (TGA) for use in Australia is An Australian Approved Name (AAN)
* The trade (proprietary) or brand name is selected by the drug company selling the drug. Protected by a trademark. So the same drug can have several trade names when produced by a number of different manufacturers, e.g. Panadol, Panamax, Dymadon and Tylenol.

Question 4

The enteral (oral) route

Answer 4

Medications absorbed via the gastrointestinal (GIT or enteral) system. The oral route suggests that, in most instances, the person will swallow the drug before it reaches the gastrointestinal tract but also includes drug administration:
* through a nasogastric tube
* via PEG, gastronomy or other enteral feeding device
Medications administered by the enteral/oral route are subject to first pass metabolism (more on this later)
Most commonly used route of administration
- Drugs administered via the enteral route can take many forms:
* Tablets
* Capsules
* Lozenges
* Liquid preparations
Advantages
* Easily administered
* Pain free
* Non invasive
* Economical
* Normally good absorption along whole length of GI tract
* Gradual increase in plasma concentration of drug

Disadvantages
* Requires patient compliance, i.e. to take the right dose at the right time
* Patient must be conscious and co-operative in order to be given the dose (except where administration is through an enteral tube)
* The medication may cause gastrointestinal irritation
* Medication effectiveness may be altered by food, gastric secretions, emotional stress or physical activity
* The drug may be denatured in the digestive tract, e.g. proteins such as insulin cannot be administered orally
* It takes longer for the drug to take effect
* The drug will be subject to first-pass metabolism (discussed later)

Question 5

Sublingual and Buccal

Answer 5

• Sublingual administration-drug placed under tongue to dissolve(disperse)
• Buccal administration-drug placed between cheek and gum
• Both routes facilitate rapid absorption of medication via the capillaries of the mucous membrane rather than being processed by the gastrointestinal system
• Both avoid first pass metabolism

Question 6

The parenteral route

Answer 6

Any method of drug administration that avoids the gastrointestinal tract
* Often refers to where an invasive procedure is used; primarily injecting directly into the body
* Most common parenteral routes include intravenous (IV), intramuscular (IM) and subcutaneous (SC)
* Includes intra-arterial and epidural (drug injected into spinal canal outside duramater)
* Also includes drug injected directly into other body cavities

Advantages
* Provides an alternative when drugs given orally are poorly absorbed, inactive or ineffective.
* The IV and intra-arterial routes provide immediate onset of action.
* The IM and SC routes can be used to achieve a slower or delayed onset of action.
* Problems with patient co-operation, compliance and conscious state can be avoided.
* Avoids first pass metabolism. (more on first pass metabolism soon)

Disadvantages
* Skill required to inject correct site using the required technique
* Aseptic technique required to avoid the risk of infection
* The onset of drug action can be rapid
* Requires accurate dosage
* It can be painful
* It is often more expensive
* May require additional equipment (e.g. I.V. cannula and tubing, plus programmable infusion pump)

Other routes of administration (Parenteral)
Inhalation (pulmonary route) - Drugs administered by gas or fine mist.
* The lungs provide a large surface area for absorption.
* Respiratory membrane and its rich capillary network allows drugs to readily enter the circulation.
* Examples include anaesthetic agents and bronchodilators administered by nebulisers or “puffers”.

Topical route – applying drug to the skin or mucous membranes.
* Used to produce local or systemic effects.
* Includes administration via skin, eyes, ears, nose, vagina and rectum.
* Medication may take the form of an ointment, transdermal patch, drops, pessaries or suppositories.
* Must be applied to intact skin.

Question 7

Pharmacokinetics

Answer 7

· Once a drug has been administered into the body, the drug must reach its molecular target
· The amount of drug that interacts with its target is influenced by how the drug is:
* Absorbed into the body
* Distributed around the body
* Metabolised by the body
* Excreted from the body

Question 8

Absorption

Answer 8

• Movement of drug from the site of administration to the systemic circulation.
  
  • Before a drug gains access to internal compartments of the body absorption must take place.
  • Most drugs are subject to absorption.
  • Exceptions include some of the parenteral injections
  • Intravascular administration means a drug will directly enter the systemic circulation, bypassing the many complications of absorption from other routes.
  • Intravascular administration includes the intravenous and intra-arterial routes.
  • These parenteral routes of administration effectively bypass absorption. Drugs administered in this way immediately commence being distributed around the body.
    Movement of drug from the site of administration to the systemic circulation.
    · Many drugs are introduced into the body from outside the blood stream, e.g. topical, oral, subcutaneous, and must first be absorbed before having any effect.
    In the case of medication(tablet) taken orally
    → disintegrated (broken down)
    → goes into solution (dissolution)
    → is absorbed from the small intestine
    → into the hepatic portal system (blood supplygliver)
    → then into systemic circulation

Question 9

Factors affecting drug absorption

Answer 9

· The formulation of a drug, i.e. oral route - a liquid medication is more rapidly absorbed than a tablet
· The route of administration
· Tissue surface area and thickness
* absorption through the small intestine (large surface area and single layer of epithelial cells) is quicker than through the local topical administration on skin (small surface area, multiple cell layers to cross)
· The blood supply at the site of administration
* Highly vascularised area (e.g. the sublingual route) →more rapid absorption vs. poorly vascularised area (e.g. subcutaneous injection) → slower absorption
* Patients with cardiovascular disease may have reduced blood circulation → slows absorption rate

Question 10

The solubility of a drug

Answer 10

• For absorption to occur, a drug must be in solution, able to cross the plasma membrane (e.g. of intestinal epithelial cells, epithelial cells of skin) and enter blood capillaries
• lipid-soluble drugs → easily cross the plasma membrane via simple diffusion → rapid absorption
• water-soluble drugs → cross the plasma membrane via facilitated diffusion or active transport → slower absorption

Question 11

Distribution

Answer 11

Distribution is the process of reversible transfer of a drug between one location and another in the body

Once the drug has reached the systemic circulation it can be distributed to various body compartments including
* fluid compartments gin particular blood
* intracellular compartments gtarget tissue plus other tissue e.g bone & fat

Depending on the type of drug, the drug may:
* be distributed to organs that are well perfused (i.e. good blood supply)
* be distributed more slowly to areas that are poorly perfused (e.g. adipose tissue)
* remain in the blood

The movement of a drug to body tissues. Depends on:
* Drug solubility (water or lipid soluble) § Cardiovascular functioning (especially cardiac output)
* Perfusion of the area
* Degree of blood flow (vascularisation)
* The permeability of the capillaries, i.e. brain vs. liver
* pH of the area
* Binding of drug to plasma proteins. Upon entering the systemic circulation:
* a proportion of drug molecules bind reversibly to plasma proteins
* a proportion of drug molecules remain “free” or unbound
* pharmacological action is exerted by unbound drug, so a high degree of plasma protein binding will affect drug efficacy.

Once “free” drug is removed from circulation (e.g. via metabolism, excretion) more protein bound drug will be released.

Question 12

Factors affecting drug distribution

Answer 12

The movement of a drug to body tissues. Depends on:
* Tissue binding. Adipose tissue.
* Lipid soluble drugs have a high affinity for adipose tissue. Low blood flow to this tissue means some drugs may be stored here.
Bone tissue.
* Some drugs have a special affinity for bone and can accumulate here.

This decreases immediate distribution. Drugs having accumulated here may be released slowly over time.

Question 13

Barriers to drug distribution

Answer 13

Blood-brain barrier.
* Made up of endothelial cells with tight intercellular junctions to protect CNS from potentially damaging microorganisms and other substances.
Placental barrier.
* Membranes and enzymes providing incomplete protection to fetal circulation.

Question 14

Metabolism

Answer 14

• Metabolism, or biotransformation, is the process where drugs are broken down into substances more easily excreted. These chemicals are termed metabolites.
  
  • The liver is the most important site of drug metabolism. Is facilitated by enzymes located here.
  • Rate of metabolism varies markedly between individuals. § Factors affecting metabolism include:
  • Genetics
  • Environmental factors
  • Other medications, diet, alcohol, activity.
  • Age and gender
  • Infants have immature liver function
  • The elderly show delayed metabolism of drugs
  • Pregnancy can alter drug metabolism
  • Disease states
• The presence of hepatic, renal or cardiovascular disease will slow metabolism

Question 15

Bioavailability

Answer 15

Refers to the amount of drug that is available to exert a pharmacological effect.
* Is the proportion (%) of the administered drug that reaches the systemic circulation.
* Bioavailability varies with route of administration
* Drugs administered orally undergo first-pass metabolism → bioavailability much lower than originally administered drug dose.
* Drugs administered intravascularly do not undergo first- pass metabolism → bioavailability is 100% of originally administered dose of medication.
Hepatic first-pass metabolism means, therefore, that the oral dose of a medication is often higher than would be given intravascularly

Question 16

Hepatic first pass metabolism

Answer 16

• Applies to enteral administration of a medication
• Medication enters stomach (if swallowed) or small intestine (via enteral feeding device)
• Some medications will require further breakdown before being absorbed by GIT mucosa into blood of surrounding capillaries
• Absorbed drug makes it way from capillaries into the hepatic portal vein for transport to the liver.
• Some drug may be lost if not absorbed from the gastrointestinal tract. Removed with faeces.
• Drugs reaching the liver undergo metabolism before reaching the systemic circulation. This is called first-pass metabolism.
• A patient takes a 100mg dose of a drug, for example.
• 80 mg of the dose is absorbed from the small intestine and reaches the liver via the hepatic portal vein → 20 mg was not absorbed from the small intestine
• The liver then metabolises the remaining 80 mg → 60 mg is irreversibly lost (eliminated)
• Only 20 % of the original dose reaches the systemic circulation
  This proportion that reaches systemic circulation is the remaining amount of drug available to exert a pharmacological effect – known as the BIOAVAILABILITY of the drug

Question 17

Excretion

Answer 17

The pharmacological effects of a drug continues until it is removed from the body.
Elimination is the irreversible loss of the drug from the plasma. Occurs via metabolism and excretion.
* Liver is the main site of elimination due to metabolism.
Excretion is the irreversible loss of the drug from the body
* Kidneys excrete most drugs and their metabolites
* Drugs can be eliminated in bile so removed from the body in faeces
* Lungs the primary route for excretion for volatile substances such as inhalation anaesthetics
* Other routes include intestine, salivary, sweat and mammary glands
The kidneys are the primary site of drug excretion from the body.
* Free unbound drug can be filtered from the blood into the renal filtrate
* Lipid soluble drugs may be reabsorbed from the renal filtrate back into systemic circulation
* Water-soluble drugs can also be secreted from the blood into the filtrate.
The process of excretion is dependent on:
* urinary pH which can range from 4.6 – 8.2
renal and cardiovascular function.

Question 18

Therapeutic range

Answer 18

The range of concentration of a drug having a high probability of producing the desired therapeutic effect and low probability of toxic effects.
* Achieved by a drug dosage regime which includes
o the amount of drug administered and
o how often the drug is administered
* Derived from information about populations of individuals and pharmacokinetic profile of the drug.
* Important to remember not everyone responds to the same drug in the same way.

The therapeutic range lies between 2 concentrations:
1. The minimum effective concentration
* Minimum amount of drug required to cause a pharmacological effect
2. The minimum toxic concentration
* Minimum amount of drug that causes a toxic effect

The therapeutic range of a drug depends on the route of administration, the pharmacokinetics of the drug and the characteristics of an individual
* Characteristics of an individual to consider
* Age
* Gender
* Health/disease status
* Cardiovascular, liver and kidney function

Question 19

Drug half-life

Answer 19

• The term half-life (T1⁄2) is defined as the time taken for the drug concentration to be reduced by 50% from its maximum concentration
• The drug half-life tells us:
• How quickly a drug is being eliminated from the plasma
• How often we need to administer a drug to keep it within the therapeutic range
• e.g. IV administration of 100 mg of a drug that has a half life of 4 h:
• After 4 h, 50 mg will remain in plasma
• After another 4 h (or 8 h in total), 25 mg will remain
• The drug should be administered at regular time intervals to keep the plasma concentration within the therapeutic range

Question 20

Rational drug use: developing a drug dosage regime

Answer 20

• Minimum effective concentration- when there is enough drug in the plasma to begin exerting a pharmacological or therapeutic effect (example seen on previous slide shows 6mg/L)
• Onset of action- time at which minimum effective concentration is reached (example seen on previous slide shows 2hrs)
• Termination of action- concentration of drug has dropped below minimum effective concentration. No longer has a therapeutic effect (8hrs)
• Duration of action- time between minimum effective concentration and termination of action. (6hrs)
• Cmax- maximum plasma concentration of drug (≃ 16mg/L)
• Tmax- time taken to reach maximum concentration of drug (time at which Cmax happens) (5hrs)
  T1/2 - time taken for drug concentration to be reduced by half ➤ 50% of maximum concentration

Question 21

Pharmacodynamics

Answer 21

• The study of how the drug effects the body is called pharmacodynamics and involves:
  
  • The effect of the drug on the body
  • The mode of drug action
• The mode of drug action depends on the drug’s molecular target:
  
  • Proteins (primary target)
  • carrier proteins
  • ion channels
  • enzymes/chemical reactions
  • receptors
• DNA, i.e. chemotherapy drugs

Question 22

Carrier proteins

Answer 22

• Drugs can alter the function of carrier proteins involved in facilitated diffusion and/or active transport
• Drugs bind to and prevent the carrier protein from moving molecules into the cell
  e.g. some antidepressants block the re-uptake of the “feel-good” neurotransmitter NA in synapses g keeping NA in the synapse and thus enhancing its effects

Question 23

Ion channels

Answer 23

• Drugs can alter the function of proteins involved in facilitated diffusion
• Drugs act on ion channels by:
• Binding to the channel (or its associated receptors), causing the channel to open or close
• Blocking the channel

Question 24

Enzymes

Answer 24

• Enzymes are biological catalysts that increase the rate of chemical reactions
• Two main types of drugs affect enzymes:
• Competitive inhibitors
• Drug binds to the enzyme active site ➤substrate cannot bind
• Slows or inhibits enzyme activity
• e.g. non-steroidal anti- inflammatory drugs (NSAIDS), Viagra, Strychnine.
• Non-competitive inhibitors
• Drug binds to the enzyme, changing its shape ➤prevents substrate from binding
• The enzyme is destroyed
• e.g. Penicllin (acts on peptidogylcan wall in bacterial cells), Cyanide (toxic to humans)

Question 25

Receptors

Answer 25

* Receptors are: - present on the cell membrane and within the cytoplasm - involved in signaling between and within cells - a major drug target * Drugs that bind receptors: * Bind in place of the natural ligand Act as either an: * Agonist - initiates or enhances the normal response * Antagonist - blocks the normal response

Question 26

Hypersensitivity

Answer 26

* Substances foreign to the body act as antigens and can stimulate the bodies immune system. * The body’s immune system showing an exaggerated response to a drug perceived as a foreign substance is known as drug hypersensitivity i.e. an allergic reaction * The most dramatic form is anaphylaxis where sudden onset of bronchospasm, vasospasm and severe hypotension can rapidly lead to death. Rare. * Some involve altered reactions to medications. * Rashes commonly seen.

Question 27

Adverse drug reaction (ADR)

Answer 27

An unintended and/or undesirable effect of a drug * Many drugs will cause some adverse effect in patients * Includes drug hypersensitivity * Requires alteration of the dosage regime or withdrawal of the medication Consequences: * Decreased effectiveness of treatment * Poor therapeutic outcomes - Prolonged illness - Increased length of hospital stay - Increased costs - Higher mortality rates Predisposing factors for ADR: * Age – elderly and neonates Twice as common and more severe in elderly * Gender – more common in females (size?) * Dose – many are dose related * Polypharmacy (taking multiple, different medications) – increases risk, especially in elderly * History – frequent presenter/chronic condition at higher risk * Genetic factors – possible liver enzyme deficiency

Question 28

Drug interactions

Answer 28

A drug-drug interaction (DDI) occurs when the pharmacological effect of one drug is altered by another drug * The effect could be an enhanced therapeutic effect of the drug, or * A decreased therapeutic effect of the drug, or * An ADR - May occur for both prescription and non- prescription medications - DDI occur frequently and result in a significant number of hospital admissions

Question 29

Drug contraindications

Answer 29

Contraindication - a factor that makes the administration of a drug undesirable or even dangerous. Factors may include: - patient statis * Premature infants, neonates and the elderly - liver and kidney function may be inefficient * Pregnant women - medications that can cross the placenta and effect the growing fetus * a current disease state * Kidney disease - clearance (excretion) will be reduced * Liver disease - metabolism and clearance (elimination) will both be affected * drug therapy with potential for interaction or adverse reaction * Digoxin and Amiodarone * Digoxin in bradycardia * These conditions determine when a drug should NOT be prescribed

Question 30

Drug transfer

Answer 30

Any drug given to a pregnant woman may reach the growing fetus via the circulation or be transferred to a neonate via breast milk during feeding e.g. codeine, aspirin, antibiotics, caffeine Factors contributing to potential harm: * Drug properties and dosage * Gestational age of the fetus 1st trimester – organ systems developing 3rd trimester – greatest placental blood flow * Drugs known to have the potential to cause harm to the fetus are referred to as teratogenic * Many healthcare providers recommend that no drug should be used during pregnancy because of potential risk to the developing fetus. * Certain conditions may require drug therapy e.g. hypertension, epilepsy, diabetes, infection. Need to balance benefit & risk.